Dose-response effects of TPI ASM8 in asthmatics after allergen.

Background: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (β(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics.

Objective: We assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC).

Oligonucleotides: New therapeutic approaches for asthma and chronic obstructive pulmonary disease.

Asthma and COPD are significant lung diseases for which anti-inflammatories, including inhaled corticosteroids and leukotriene- targeted drugs, represent a key element of current therapy. Oligonucleotides comprise a diverse family of emerging drug candidates for the treatment of these diseases. There is a commonality in the chemistry of oligonucleotide drug molecules but, importantly, individual candidates are distinct in their molecular targets and also possess different mechanisms of action.

WITHDRAWN: The Inhalers of the Future? A Review of Dry Powder Devices on the Market Today.

The publisher regrets that this is an accidental duplication of an article that has already been published inPulm. Pharmacol. Ther.

Evidence based guidelines--a step too far?

The growth of clinical guidelines has helped to improve the standard of patient care with the archetypal document being the British Thoracic Society's guidelines on asthma management. In recent years however the fashion has evolved to style guidelines according to the tenants of 'evidence based medicine'. We examine the evidence behind this fashion and conclude that there is a grave danger of bias and distortion of the data from this approach.

Protection against methacholine-induced bronchospasm: salbutamol pMDI versus Clickhaler DPI.

Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy. This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler) with a reference salbutamol pMDI (Ventolin).

The inhalers of the future? A review of dry powder devices on the market today.

International agreements to ban the use of environmentally damaging chlorofluorocarbons (CFCs) have signalled an end to the traditional CFC-propelled pressurised metered dose inhaler (pMDI) which has long been the mainstay of topical asthma therapy. The need for acceptable and cost-effective replacement inhalers, combined with opportunities to develop generic formulations of patent-expired drugs, has fueled a lively response from the pharmaceutical industry. Improvements in pMDI design and reformulation with propellants such as hydrofluoroalkanes may offer significant advantages over CFC-pMDIs and prolong the widespread use of pressurised drug delivery systems for many years to come.

Inspiratory flow rate through a dry powder inhaler (Clickhaler) in children with asthma.

Dry powder inhalers (DPIs) are increasingly being used to deliver drugs for the treatment of asthma. Both the aerosolization and delivery of the drug from a DPI to the lung are dependent on an adequate inspiratory effort from the patient, and it is well-known that the air flow achieved early in the inspiratory profile is important in determining particle size distribution from the inhaler. The present study assessed the peak inspiratory flow (PIF) generated through the Clickhaler DPI, and the early inspiratory flow at 150 mL of inspired volume (IF(150)), in asthmatic children.

Clickhaler dry powder inhaler: focussed in vitro proof of principle evaluation of a new chemical entity for asthma.

A new chemical entity (NCE) was evaluated in the Clickhaler (Innovata Biomed Ltd.) dry powder inhaler, a reservoir-based multidose delivery system. The standard device metering system was modified to handle higher doses (nominally 20 mm(3) of lactose based blend).

Gamma scintigraphic evaluation of a novel budesonide dry powder inhaler using a validated radiolabeling technique.

A scintigraphic study was carried out to compare the lung deposition of budesonide delivered via Clickhaler and Turbuhaler dry powder inhalers in healthy volunteers. Validation of Technetium-99m ((99m)Tc) radiolabeling of the budesonide/lactose blend used in the Clickhaler and excipient-free budesonide used in the Turbuhaler was carried out using a multistage liquid impinger, and compared with reference unlabeled devices. Budesonide was quantified using high-performance liquid chromatography and (99m)Tc by scintillation counting.

Design, development and performance of a novel multidose dry-powder inhaler.

The authors describe the design and development of a breath-actuated multidose dry-powder inhaler and summarize the in vitro and in vivo data demonstrating its robustness and performance in the laboratory and during clinical use. Drugs for the treatment of asthma--including budesonide, beclomethasone dipropionate and salbutamol--when formulated with lactose powder as a carrier and dispensed via this device, have exhibited clinical efficacy and safety profiles comparable with standard pressurized metered-dose inhalers and dry-powder formulations.

Reproducibility of bronchodilator response for a reservoir dry powder inhaler following routine clinical use.

The performance of dry powder inhaler (DPI) devices, particularly reservoir DPIs, may be influenced by environmental conditions. This study compared the bronchodilator efficacy and in vitro aerosol characteristics of salbutamol, delivered via a novel reservoir DPI (Clickhaler) and a conventional pressurized metered-dose inhaler (MDI) before and after use of the DPI in clinical practice. Following a screening visit, patients received cumulative doses of salbutamol (100, 200, and 400 microg) via DPI or MDI on separate days in a double-blind, crossover design before and after a 4-week period, during which the DPI was used as the patients' first-line bronchodilator.

Clickhaler (a novel dry powder inhaler) provides similar bronchodilation to pressurized metered-dose inhaler, even at low flow rates.

Study Objective: Comparison of the bronchodilator response to an albuterol novel dry powder inhaler (DPI) (Clickhaler [CH]; ML Laboratories PLC; St. Albans, UK) activated at various inspiratory flow rates and to an albuterol pressurized metered-dose inhaler (pMDI) by patients with moderate to moderately severe stable asthma.

Design: Randomized, double-blind, placebo-controlled comparison of the bronchodilator response to albuterol DPI (200 microg) at inspiratory flow rates of approximately 15, 30, and 60 L/min in patients with stable asthma with demonstrated reversibility to albuterol.

Furosemide decreases the sensitivity of glucose transport to insulin in skeletal muscle in vitro.

The effects of the diuretic furosemide on the sensitivity of glucose disposal to insulin were investigated in rat soleus muscle in vitro. At basal levels of insulin, the rates of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation and lactate formation were not affected significantly by furosemide (0.5 mmol/l).

Use of whole-body plethysmography to compare bronchodilator inhaler efficacy.

Whole-body plethysmography is not included in guidelines from regulatory authorities for the development of treatments or delivery devices for lung disease, despite its potential advantages compared to spirometry. Two separate studies were undertaken to assess the use of specific airway conductance (sGaw) as a pharmacodynamic endpoint for the comparison of two bronchodilator delivery systems (a novel dry powder inhaler and a standard metered dose inhaler). The first pilot study involved delivery of a single dose of salbutamol (200 micrograms) to 12 healthy volunteers and determination of sGaw up to 120 min after treatment.

The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats.

The effects of insulin on the rates of glucose disposal were studied in soleus muscles isolated from hyper- or hypothyroid rats. Treatment with triiodothyronine for 5 or 10 days decreased the sensitivity of glycogen synthesis but increased the sensitivity of lactate formation to insulin. The sensitivity of 3-O methylglucose to insulin was increased only after 10 days of treatment and was accompanied by an increase in the sensitivity of 2-deoxyglucose phosphorylation; however, 2-deoxyglucose and glucose 6-phosphate in response to insulin remained unaltered.

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler.

Aims: The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.

Methods: A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30 min following inhalation of 2 x 100 micrograms salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin (Allen and Hanburys Ltd, UK) MDI in 10 volunteers.

Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle.

GENBANK/dy examines the mechanisms of glucocorticoid-induced insulin resistance in rat soleus muscle. Glucocorticoid excess was induced by administration of dexamethasone to rats for 5 days. Dexamethasone decreased the sensitivity of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation, glycogen synthesis and glucose oxidation to insulin.

Growth hormone suppression and glutamine flux associated with cardiac surgery.

Pharmacological doses of growth hormone (GH) in humans and rats increase plasma and muscle glutamine values. As major surgery results in a physiological rise in serum GH concentration, we investigated whether this physiological increase in GH altered glutamine metabolism. Eighteen patients undergoing coronary artery bypass graft (CABG) surgery were randomly assigned to receive somatostatin, 100 micrograms subcutaneously at induction of anaesthesia and 8 hourly for 48 h, or placebo.

Studies on the effects of growth hormone administration in vivo on the rates of glucose transport and utilization in rat skeletal muscle.

The effects of growth hormone (GH) administration to rats in vivo on the sensitivity of the rate of glucose utilization to insulin were studied in soleus muscles isolated from these rats. A single injection of GH did not increase the rate of glucose transport within 1-2 h. However, 12 h after, the rate of glucose transport was increased at 10 mU insulin l-1 and was accompanied by a similar increase in the rate of lactate formation but no change in the rate of glycogen synthesis.

The effects of growth hormone administration in vivo on skeletal muscle glutamine metabolism of the rat.

Human growth hormone administration to the rat for 3 or 10 days increased the concentrations of glutamine in both skeletal muscle and plasma and the rate of glutamine release was increased from muscle isolated from rats treated with growth hormone for 3 days. Growth hormone may therefore play an important role in the control of glutamine metabolism in muscle.

The effects of growth hormone and insulin-like growth factors I and II on glutamine metabolism by skeletal muscle of the rat in vitro.

Soleus muscle preparations of the rat were incubated in the presence of growth hormone, IGF-I or IGF-II. Growth hormone (10 and 100 ng/ml) increased, but IGF-I and IGF-II were without effect on the concentration of glutamine in soleus muscle. Growth hormone was without effect on the rate of release of glutamine from muscle.

Effects of glucocorticoids on lymphocyte metabolism.

The immunosuppressive effect of glucocorticoids has been widely reported; however, the mechanism of action of these hormones on the immune system has not been fully established. In the present study, the effect of glucocorticoids on glucose, glutamine, and pyruvate metabolism in lymph node lymphocytes was investigated. Addition of dexamethasone to the incubation medium did not alter glucose and glutamine metabolism but inhibited pyruvate utilization by 40%.

Plasma amino acid concentrations in the overtraining syndrome: possible effects on the immune system.

Overtraining and long-term exercise are associated with an impairment of immune function. We provide evidence in support of the hypothesis that the supply of glutamine, a key fuel for cells of the immune system, is impaired in these conditions and that this may contribute to immunosuppression. Plasma glutamine concentration was decreased in overtrained athletes and after long-term exercise (marathon race) and was increased after short-term, high intensity exercise (sprinting).

Acute ethanol administration and the metabolism of glutamine by skeletal muscle of the rat: implications for ethanol-induced reductions in protein synthesis.

The effect of acute ethanol administration (75 mmol/kg) on the metabolism of glutamine by skeletal muscle of the rat was studied in order to investigate the hypothesis that the concentration of this amino acid in muscle controls the rate of protein synthesis. Ethanol administration was without effect on the concentration of glutamine in EDL (extensor digitorum longus) and plantaris muscles (Type II fibre-rich muscles), but increased the concentration in soleus muscle (Type I fibre-rich muscle). The rate of release of glutamine was increased from EDL muscle, but unchanged from soleus muscle of treated animals.